Nna1 Mediates Purkinje Cell Dendritic Development via Lysyl Oxidase Propeptide and NF-κB Signaling

SummaryThe molecular pathways controlling cerebellar Purkinje cell dendrite formation and maturation are poorly understood. The Purkinje cell degeneration (pcd) mutant mouse is characterized by mutations in Nna1, a gene discovered in an axonal regenerative context, but whose actual function in development and disease is unknown. We found abnormal development of Purkinje cell dendrites in postnatal pcdSid mice and linked this deficit to a deletion mutation in exon 7 of Nna1. With single cell gene profiling and virus-based gene transfer, we analyzed a molecular pathway downstream to Nna1 underlying abnormal Purkinje cell dendritogenesis in pcdSid mice. We discovered that mutant Nna1 dramatically increases intranuclear localization of lysyl oxidase propeptide, which interferes with NF-κB RelA signaling and microtubule-associated protein regulation of microtubule stability, leading to underdevelopment of Purkinje cell dendrites. These findings provide insight into Nna1's role in neuronal development and why its absence renders Purkinje cells more vulnerable

SN 2009bb: a Peculiar Broad-Lined Type Ic Supernova

Ultraviolet, optical, and near-infrared photometry and optical spectroscopy of the broad-lined Type Ic supernova (SN) 2009bb are presented, following the flux evolution from -10 to +285 days past B-band maximum. Thanks to the very early discovery, it is possible to place tight constraints on the SN explosion epoch. The expansion velocities measured from near maximum spectra are found to be only slightly smaller than those measured from spectra of the prototype broad-lined SN 1998bw associated with GRB 980425. Fitting an analytical model to the pseudo-bolometric light curve of SN 2009bb suggests that 4.1+-1.9 Msun of material was ejected with 0.22 +-0.06 Msun of it being 56Ni. The resulting kinetic energy is 1.8+-0.7x10^52 erg. This, together with an absolute peak magnitude of MB=-18.36+-0.44, places SN 2009bb on the energetic and luminous end of the broad-lined Type Ic (SN Ic) sequence. Detection of helium in the early time optical spectra accompanied with strong radio emission, and high metallicity of its environment makes SN 2009bb a peculiar object. Similar to the case for GRBs, we find that the bulk explosion parameters of SN 2009bb cannot account for the copious energy coupled to relativistic ejecta, and conclude that another energy reservoir (a central engine) is required to power the radio emission. Nevertheless, the analysis of the SN 2009bb nebular spectrum suggests that the failed GRB detection is not imputable to a large angle between the line-of-sight and the GRB beamed radiation. Therefore, if a GRB was produced during the SN 2009bb explosion, it was below the threshold of the current generation of gamma-ray instruments.Comment: Accepted for publication in Ap

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Whole-Community Facilitation Regulates Biodiversity on Patagonian Rocky Shores

Understanding the factors that generate and maintain biodiversity is a central goal in ecology. While positive species interactions (i.e., facilitation) have historically been underemphasized in ecological research, they are increasingly recognized as playing important roles in the evolution and maintenance of biodiversity. Dominant habitat-forming species (foundation species) buffer environmental conditions and can therefore facilitate myriad associated species. Theory predicts that facilitation will be the dominant community-structuring force under harsh environmental conditions, where organisms depend on shelter for survival and predation is diminished. Wind-swept, arid Patagonian rocky shores are one of the most desiccating intertidal rocky shores ever studied, providing an opportunity to test this theory and elucidate the context-dependency of facilitation.Surveys across 2100 km of southern Argentinean coastline and experimental manipulations both supported theoretical predictions, with 43 out of 46 species in the animal assemblage obligated to living within the matrices of mussels for protection from potentially lethal desiccation stress and predators having no detectable impact on diversity.These results provide the first experimental support of long-standing theoretical predictions and reveal that in extreme climates, maintenance of whole-community diversity can be maintained by positive interactions that ameliorate physical stress. These findings have important conservation implications and emphasize that preserving foundation species should be a priority in remediating the biodiversity consequences of global climate change

KiDS+VIKING+GAMA:Testing semi-analytic models of galaxy evolution with galaxy-galaxy-galaxy lensing

Several semi-analytic models (SAMs) try to explain how galaxies form, evolve and interact inside the dark matter large-scale structure. These SAMs can be tested by comparing their predictions for galaxy-galaxy-galaxy-lensing (G3L), which is weak gravitational lensing around galaxy pairs, with observations. We evaluate the SAMs by Henriques et al. (2015; H15) and by Lagos et al. (2012; L12), implemented in the Millennium Run, by comparing their predictions for G3L to observations at smaller scales than previous studies and also for pairs of lens galaxies from different populations. We compare the G3L signal predicted by the SAMs to measurements in the overlap of the Galaxy And Mass Assembly survey (GAMA), the Kilo-Degree Survey (KiDS), and the VISTA Kilo-degree Infrared Galaxy survey (VIKING), splitting lens galaxies into two colour and five stellar-mass samples. Using an improved G3L estimator, we measure the three-point correlation of the matter distribution for mixed lens pairs with galaxies from different samples, and unmixed lens pairs with galaxies from the same sample. Predictions by the H15 SAM agree with the observations for all colour-selected and all but one stellar-mass-selected sample with 95% confidence. Deviations occur for lenses with stellar masses below $9.5h^{-2}\mathrm{M}_\odot$ at scales below $0.2h^{-1}\mathrm{Mpc}$. Predictions by the L12 SAM for stellar-mass selected samples and red galaxies are significantly higher than observed, while the predicted signal for blue galaxy pairs is too low. The L12 SAM predicts more pairs of small stellar-mass and red galaxies than the H15 SAM and the observations, as well as fewer pairs of blue galaxies. Likely explanations are different treatments of environmental effects by the SAMs and different models of the initial mass function. We conclude that G3L provides a stringent test for models of galaxy formation and evolution.Comment: 14 pages, 8 figures, replaced with version accepted to Astronomy & Astrophysics after considering referees comment

The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5A Nuclear Receptors in Fish and Mammalian Cells

Atrazine (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 µg/L), and increased the ratio of female to male fish (22 µg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHß, INHα, αGSU, and 11ß-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies